Formulations comprising human anti-RANKL monoclonal antibodies, and methods of using the same

Abstract

Disclosed herein are aqueous pharmaceutical formulations comprising denosumab or another human anti-RANKL monoclonal antibody or portion thereof, and characteristics of pH, buffer systems, and amino acid aggregation inhibitors. Also disclosed are presentation of the formulation for use, e.g. in a single-use vial, single-use syringe, or glass container, methods of using the formulations and articles for preventing or treating diseases, and related kits.

What is claimed is: 
     
       1. An aqueous pharmaceutical formulation comprising (i) a human anti-human receptor activator of nuclear factor kappa-B ligand (anti-RANKL) monoclonal antibody, or an antigen-binding portion thereof and (ii) an amino acid aggregation inhibitor, wherein the amino acid aggregation inhibitor is (a) an aromatic amino acid comprising a phenyl or an indole or (b) a hydrophobic amino acid which has a score greater than about 2.5 on the Kyte and Doolittle hydrophobicity scale. 
     
     
       2. The aqueous pharmaceutical formulation of  claim 1 , wherein the aromatic amino acid is L-phenylalanine or L-tryptophan. 
     
     
       3. The aqueous pharmaceutical formulation of  claim 1 , wherein the aromatic amino acid comprises a C1-C6 alkyl chain between the alpha carbon and the phenyl or indole. 
     
     
       4. The aqueous pharmaceutical formulation of  claim 3 , wherein the hydrophobic amino acid is L-valine, L-leucine, or L-isoleucine. 
     
     
       5. The aqueous pharmaceutical formulation of  claim 1 , comprising about 5 mM to about 300 mM of the amino acid aggregation inhibitor. 
     
     
       6. The aqueous pharmaceutical formulation of  claim 5 , comprising about 5 mM to about 180 mM amino acid aggregation inhibitor, optionally, L-phenylalanine. 
     
     
       7. The aqueous pharmaceutical formulation of  claim 6 , comprising about 5 mM to about 100 mM amino acid aggregation inhibitor, optionally, L-phenylalanine. 
     
     
       8. The aqueous pharmaceutical formulation of  claim 1  (i) comprising only one amino acid aggregation inhibitor, (ii) wherein the molar ratio of the amino acid aggregation inhibitor to the anti-RANKL antibody is about 10 to 200, and/or (iii) further comprising a tonicity modifier, optionally, selected from the group consisting of: sorbitol, mannitol, sucrose, trehalose, glycerol, and combinations thereof. 
     
     
       9. The aqueous pharmaceutical formulation of  claim 1 , having a pH in a range of about 5.0 to about 5.4. 
     
     
       10. The aqueous pharmaceutical formulation of  claim 1 , (i) having a viscosity that is not more than about 6 cP at 5° C., optionally, wherein the viscosity is about 4.5 cP to about 5.5 cP, (ii) having a conductivity of about 500 μS/cm to about 2000 μS/cm, (iii) having an osmolality in a range of about 200 mOsm/kg to about 500 mOsm/kg, and/or (iv) comprising less than 2% high molecular weight species (HMWS) and/or more than 98% of the antibody main peak, as measured by SE-UHPLC, following storage at about 2° C. to about 8° C. for at least 12 months, 24 months, or 36 months. 
     
     
       11. The aqueous pharmaceutical formulation of  claim 7 , comprising about 25 mM to about 90 mM amino acid aggregation inhibitor, optionally, L-phenylalanine. 
     
     
       12. The aqueous pharmaceutical formulation of  claim 11 , comprising about 20 mM to about 50 mM amino acid aggregation inhibitor. 
     
     
       13. The aqueous pharmaceutical formulation of  claim 9 , wherein the pH is about 5.0 to about 5.2. 
     
     
       14. The aqueous pharmaceutical formulation of  claim 10 , wherein the osmolality is about 225 mOsm/kg to about 400 mOsm/kg. 
     
     
       15. The aqueous pharmaceutical formulation of  claim 14 , wherein the osmolality is about 250 mOsm/kg to about 350 mOsm/kg. 
     
     
       16. The aqueous pharmaceutical formulation of  claim 1 , comprising less than 2% high molecular weight species (HMWS) and/or more than 98% of the antibody main peak, as measured by SE-UHPLC, following storage at about 20° C. to about 30° C. for about 1 month. 
     
     
       17. The aqueous pharmaceutical formulation of  claim 1 , comprising less than 2% high molecular weight species (HMWS) and/or more than 98% of the antibody main peak, as measured by SE-UHPLC, following storage at about 2° C. to about 8° C. for at least 12 months, 24 months, or 36 months and a second storage at about 20° C. to about 30° C. for about 1 month. 
     
     
       18. The aqueous pharmaceutical formulation of  claim 1 , comprising less than 2% high molecular weight species (HMWS) and/or more than 98% of the antibody main peak, as measured by SE-UHPLC, following storage at about 37° C. for about one month or about 30° C. for 3 months. 
     
     
       19. The aqueous pharmaceutical formulation of  claim 1 , wherein the concentration of the antibody or antigen-binding portion thereof is greater than 70 mg/mL. 
     
     
       20. The aqueous pharmaceutical formulation of  claim 19 , wherein the concentration of the antibody or antigen-binding portion thereof is less than about 300 mg/mL. 
     
     
       21. The aqueous pharmaceutical formulation of  claim 20 , wherein the concentration of the antibody or antigen-binding portion thereof is less than about 200 mg/mL. 
     
     
       22. The aqueous pharmaceutical formulation of  claim 21 , wherein the concentration of the antibody or antigen-binding portion thereof is about 75 mg/mL to about 200 mg/mL. 
     
     
       23. The aqueous pharmaceutical formulation of  claim 22 , wherein the concentration of the antibody or antigen-binding portion thereof is about 100 mg/mL to about 140 mg/mL. 
     
     
       24. The aqueous pharmaceutical formulation of  claim 1 , further comprising a buffer and/or a surfactant. 
     
     
       25. The aqueous pharmaceutical formulation of  claim 24 , wherein the buffer is acetate or glutamate. 
     
     
       26. The aqueous pharmaceutical formulation of  claim 25 , comprising about 5 mM to about 60 mM buffer. 
     
     
       27. The aqueous pharmaceutical formulation of  claim 26 , comprising acetate buffer about 16 mM to about 41 mM acetate buffer. 
     
     
       28. The aqueous pharmaceutical formulation of  claim 24 , wherein the surfactant is polysorbate 20. 
     
     
       29. The aqueous pharmaceutical formulation of  claim 24 , comprising at least about 0.004 (w/v) % surfactant and less than 0.15 (w/v) % surfactant. 
     
     
       30. The aqueous pharmaceutical formulation of  claim 8 , comprising about 2.0 (w/w) % to about 5.0 (w/w) % sorbitol. 
     
     
       31. The aqueous pharmaceutical formulation of  claim 1 , wherein the anti-RANKL antibody is an IgG. 
     
     
       32. The aqueous pharmaceutical formulation of  claim 31 , wherein the anti-RANKL antibody is an IgG 2 . 
     
     
       33. The aqueous pharmaceutical formulation of  claim 1 , wherein the anti-RANKL antibody, or antigen-binding portion thereof, comprises (A) a light chain variable domain comprising a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a light chain variable domain comprising a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 6, and a light chain variable domain comprising a light chain CDR3 comprising the amino acid sequence of SEQ ID NO:7; and (B) a heavy chain variable domain comprising a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 8, a heavy chain variable domain comprising a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a heavy chain variable domain comprising a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 10. 
     
     
       34. The aqueous pharmaceutical formulation of  claim 33 , wherein the anti-RANKL antibody, or antigen-binding portion thereof, comprises a light chain variable region of SEQ ID NO: 1 and a heavy chain variable region of SEQ ID NO: 2. 
     
     
       35. The aqueous pharmaceutical formulation of  claim 34 , wherein the anti-RANKL antibody, or antigen-binding portion thereof, comprises a light chain of SEQ ID NO: 13 and a heavy chain of SEQ ID NO: 14. 
     
     
       36. The aqueous pharmaceutical formulation of  claim 12 , comprising about 20 mM to about 50 mM L-phenylalanine or L-tryptophan. 
     
     
       37. A container, optionally, a vial, pre-filled syringe (PFS), or glass container containing an aqueous pharmaceutical formulation of  claim 1 . 
     
     
       38. A method of treating a skeletal-related event (SRE), a giant cell tumor of bone, hypercalcemia, or osteoporosis or increasing bone mass, in a subject, comprising administering to the subject the aqueous pharmaceutical formulation of  claim 1 . 
     
     
       39. The method of  claim 38 , wherein the method comprises (a) treatment of an SRE in a subject with bone metastases from solid tumors, (b) treatment of an SRE in a subject who is an adult or a skeletally mature adolescent with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity, (c) treatment of hypercalcemia of malignancy refractory to bisphonsphonate therapy in a subject, (d) treatment of an SRE in a subject with multiple myeloma or with bone metastases from a solid tumor, (e) treatment of osteoporosis of postmenopausal women at high risk for fracture, (f) treatment to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer, (g) treatment to increase bone mass in men at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer, (h) treatment to increase bone mass in men with osteoporosis at high risk for fracture, (i) therapy with calcium or vitamin D. 
     
     
       40. A method of making a stable, aqueous pharmaceutical formulation comprising a human anti-human receptor activator of nuclear factor kappa-B ligand (anti-RANKL) monoclonal antibody, or an antigen-binding portion thereof, comprising combining the anti-RANKL monoclonal antibody, or antigen-binding portion thereof, at a concentration greater than 70 mg/mL with an amino acid aggregation inhibitor, a buffer, a surfactant, and optionally, a tonicity modifier, wherein the amino aggregation inhibitor is (a) an aromatic amino acid comprising a phenyl or an indole or (b) a hydrophobic amino acid which has a score greater than about 2.5 on the Kyte and Doolittle hydrophobicity scale. 
     
     
       41. A stable, aqueous pharmaceutical formulation made according to  claim 40 . 
     
     
       42. A method of improving the stability of an aqueous pharmaceutical formulation comprising a human anti-human receptor activator of nuclear factor kappa-B ligand (anti-RANKL) monoclonal antibody or an antigen-binding portion thereof, at a concentration of greater than 70 mg/mL, comprising:
 preparing said aqueous pharmaceutical formulation comprising said human anti-human receptor activator of nuclear factor kappa-B ligand (anti-RANKL) monoclonal antibody or an antigen-binding portion thereof at a pH in a range of about 5.0 to less than 5.2 or in admixture with an amino acid aggregation inhibitor, wherein the amino aggregation inhibitor is (a) an aromatic amino acid comprising a phenyl or an indole or (b) a hydrophobic amino acid which has a score greater than about 2.5 on the Kyte and Doolittle hydrophobicity scale, 
 wherein said aqueous pharmaceutical formulation demonstrates improved stability at the pH in a range of about 5.0 to less than 5.2 compared to an equivalent aqueous pharmaceutical formulation that is not at a pH in a range of about 5.0 to less than 5.2 or with the amino acid aggregation inhibitor compared to an equivalent aqueous pharmaceutical formulation without the amino acid aggregation inhibitor.